Gray C A, Bazer F W, Spencer T E
Center for Animal Biotechnology and Genomics and the Department of Animal Science, Texas A&M University, College Station, Texas 77843-2471, USA.
Biol Reprod. 2001 Mar;64(3):797-804. doi: 10.1095/biolreprod64.3.797.
Endometrial glands are present in all mammalian uteri and produce secretions that are hypothesized to support conceptus (i.e., embryo/fetus and placental membranes) survival and development. In sheep, endometrial gland morphogenesis occurs postnatally and can be epigenetically ablated by chronic neonatal exposure to a progestin from birth, thereby producing an adult uterine gland knock-out (UGKO) phenotype. This study determined the long-term effects of neonatal progestin exposure on adult ovine reproductive tract structure and function. Neonatal ewes were exposed to norgestomet (Nor) from birth to 32 wk of age. Unexposed ewes served as controls. After puberty, adult Nor-treated (n = 6) and control (n = 6) ewes were repeatedly bred at estrus (Day 0) to intact rams of proven fertility. In contrast to a pregnancy rate of 80% for control ewes, pregnancy was never detected on Day 25 after mating (or thereafter) in bred UGKO ewes. Control and Nor-treated ewes were then bred and necropsied on Day 9. Similar numbers of hatched blastocysts were present in uterine flushings from control and Nor-treated ewes. Weights of the ovaries and cervices were not affected by treatment. No histoarchitectural differences between control and Nor-treated ewes were detected for ovaries, oviducts, cervices, or vaginae. However, uterocervical and uterine weight as well as uterine horn length were less for Nor-treated ewes. The uteri of Nor-treated ewes were devoid of endometrial glands and lacked the stromal delineation characteristic of intercaruncular endometrium in control ewes. Endometrial width, area, and lumenal epithelial length were decreased in uteri from Nor-treated ewes, but myometrial width and morphology were not affected. Expression of a number of mRNAs that are expressed predominantly in the endometrial epithelia was not different between uteri from control and from Nor-treated ewes. Collectively, these results indicate that neonatal exposure of ewes to a progestin from birth appears to only affect development of the uterus and not any extrauterine reproductive tract tissues. The infertility of the UGKO ewes appears to result from a lack of endometrial glands and, by extension, of their secretions that are required to support growth and development of peri-implantation conceptuses.
子宫内膜腺体存在于所有哺乳动物的子宫中，并产生分泌物，据推测这些分泌物可支持孕体（即胚胎/胎儿和胎盘膜）的存活与发育。在绵羊中，子宫内膜腺体形态发生于出生后，出生后长期暴露于孕激素可通过表观遗传方式消除这种形态发生，从而产生成年子宫腺体敲除（UGKO）表型。本研究确定了新生期暴露于孕激素对成年绵羊生殖道结构和功能的长期影响。新生母羊从出生到32周龄暴露于诺孕美特（Nor）。未暴露的母羊作为对照。青春期后，成年期接受诺孕美特处理的母羊（n = 6）和对照母羊（n = 6）在发情期（第0天）反复与经证实有生育能力的完整公羊交配。与对照母羊80%的妊娠率相比，交配后第25天（或之后）在经交配的UGKO母羊中从未检测到妊娠。然后在第9天对对照母羊和接受诺孕美特处理的母羊进行交配和剖检。对照母羊和接受诺孕美特处理的母羊子宫冲洗液中存在数量相似的孵化囊胚。卵巢和子宫颈的重量不受处理影响。在卵巢、输卵管、子宫颈或阴道方面，未检测到对照母羊和接受诺孕美特处理的母羊之间存在组织架构差异。然而，接受诺孕美特处理的母羊子宫颈和子宫的重量以及子宫角长度较小。接受诺孕美特处理的母羊子宫没有子宫内膜腺体，且缺乏对照母羊子宫肉阜间子宫内膜特有的基质分界。接受诺孕美特处理的母羊子宫的子宫内膜宽度、面积和腔上皮长度减小，但子宫肌层宽度和形态不受影响。在对照母羊和接受诺孕美特处理的母羊子宫中，一些主要在内膜上皮中表达的mRNA的表达没有差异。总体而言，这些结果表明，新生母羊从出生起暴露于孕激素似乎仅影响子宫的发育，而不影响任何子宫外生殖道组织。UGKO母羊的不育似乎是由于缺乏子宫内膜腺体，进而缺乏支持着床前孕体生长和发育所需的分泌物所致。
